Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.646796
Title: Sirolimus liposomal formulations for targeting of cancer tumours
Author: Onyesom, Ichioma
ISNI:       0000 0004 5363 4154
Awarding Body: University of Greenwich
Current Institution: University of Greenwich
Date of Award: 2014
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Abstract:
In clinical trials, sirolimus (rapamycin, a macrocyclic lactone) has been shown to exhibit antitumor activity across a variety of human cancers by binding to and inhibiting the activation of the mammalian target of rapamycin (mTOR), thus preventing cell cycle progression from the G1 to S phase. Inhibitors of mTOR have received regulatory approval as immunosuppressive agents for the treatment of allograft rejection and as antitumor agents for kidney cancer (Rapamune®). In these clinical trials tumour cell proliferation was dramatically reduced without sirolimus being formulated in a drug carrier. The more challenging question is whether strategies can be developed to improve the delivery of sirolimus directly to tumour cells and maximize mTOR inhibition? The aim of the research reported herein was to develop, characterise and evaluate the anti-cancer activity of sirolimus loaded liposome formulations. Liposome-drug formulations were prepared using the thin film hydration method and were characterised using particle size analysis, atomic force icroscopy (AFM), differential scanning calorimetry (DSC) and X-ray photoelectron spectroscopy (XPS). The particle size analysis of the liposome formulations showed that the liposome-drug formulations were stable over a 6 month period of time. Further characterization of the liposome-drug formulations using XPS and DSC studies demonstrated the incorporation of the drug (sirolimus) in the liposome bilayer. In order to ascertain the anti-tumour activity of the sirolimus formulations, in-vitro studies using MTT assays were carried out on human breast cancer cell lines (MCF-7 and BT-474). The cytotoxicity studies using pure sirolimus showed anti-proliferative action at concentrations above 40 μg/mL and the formulated liposome formulations also demonstrated anti-proliferative effects when incubated with the cancer cells. Parameters such as lipid composition, incubation time and drug loading were established as important factors that play a key role in the therapeutic efficacy of the sirolimus loaded liposomes. Fluorescent images obtained from the cellular uptake and apoptosis studies also provided supporting data which demonstrated the anti-proliferative effect of the liposome formulations. In addition, sirolimus was designed to actively target breast cancer cells by conjugating transferrin on the surface of the sirolimus loaded liposomes. Both in-vitro and in-vivo studies of the conjugated sirolimus formulations demonstrated the formulation to be more effective in inducing anti-proliferative effects compared to the passive formulation (non-conjugated sirolimus loaded liposomes). Sirolimus loaded liposome anticancer activity towards prostate cancer cell lines (LNCAP and DU-145) has also been evaluated. Similar results to the breast cancer studies were obtained; specific parameters were also shown to influence the anti-proliferative efficacy of the sirolimus liposome formulations in prostate cancer cells.
Supervisor: Douroumis, Dionysios; Chowdhry, Babur Sponsor: University of Greenwich
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.646796  DOI: Not available
Keywords: RM Therapeutics. Pharmacology
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